ADNI BiomarkADNI Biomark

Leslie MJohn Q Tr

ADNI Steering Committee Mee

ker Core reportker Core report

M Shawrojanowski

ting, Los Angeles, April 9, 2011

DiscloDisclo

Les Shaw & John Trojanowski:Les Shaw & John Trojanowski:Grant support: ADNI 1, ADNI GO

Pfizer/UPenn RBM stu

L ShLes Shaw:Technical advisory board membe

osuresosures

O, ADNI 2, NIA; dies

ership: Innogenetics

The Penn Biomarker Core Of ADNI‐1, ADNI‐GO And AProgress In Biomarker Research Summarized by  Geor

George Poste, Nature, 469:156‐15

ADNI‐2 Is Addressing Concerns About Dismal rge Poste (Former GSK CEO)  

“A DROP IN THE OCEAN”OCEAN”Estimated number of papers documenting thousands of claimedthousands of claimed biomarkers  = 150,000Estimated number of biomarkers routinelybiomarkers routinely used in the clinic = 100

57, 13 Jan, 2011

Pre‐Analytical IssCSF & Plasma Coll

CSFFro

Avera

• After overnight fast• Collect into polypropylene tube• Transfer to polypropylene transfer tube• No centrifugation

160

Avera(m

95% C

• No centrifugation• Freeze at site, thaw & aliquot at UPenn, 

storage at ‐80 0C

100

120

140

Freq

uenc

y

40

60

80

F

10 20 30 40 50 60 70 80 90 100 110 10

20

Number of biofluids collected as of 4/1/2011:  13,96Number of aliquots in biofluid bank:  160,478

sues are Critical: lections For ADNI

F and Plasma samplesom collection to freezing

CSF BL

CSF through year 4 Plasma through year 4

N 948 2621

age time CSF BLCSF M12CSF 24CSF36CSF 48Plasma BLPlasma M12

age time mins) 35.11 67.94

CI (mins) 32.46-37.78 66.32-69.57

Plasma M24Plasma M36Plasma M48

Pl

Plas

Plasma

Plasma M

Plasma M

4

120 130 140 150 160 170 180 190 200 >240

CSF BL

CSF M

12

CSF 24

CSF36

CSF 48

asma BL

sma M

12

a M24

M36

48

Time (mins)Time (mins)

64

Efforts underway to imEfforts underway to im

• ADNI • Alz Assn International qc program• CAMD• UPenn/Wash U collaboration on • Collaborative studies between la

–With Mayo Clinic (Ron Petersen &–With Japan ADNI (Hiroyuki Arai, R

• UPenn/BIOCARD collaboration wUPenn/BIOCARD collaboration w• Innogenetics‐sponsored workgro

mprove standardizationmprove standardization

m

ELISA/xMAP/PiB relationshipsbs for xMAP immunoassay:

& Roy Dyer)Ryosun Kuwano & Takeshi Iwatsubo)with Marilyn Albertswith Marilyn Albertsoup on standardization guidelines

Qualification of the analytical aQualification of the analytical abiomarker ana

Leslie M Shaw • Hugo Vanderstichele • MalgoLeslie M. Shaw • Hugo Vanderstichele • MalgoCoart • Kaj Blennow • Holly Soares • Adam J. SSiemers • William Potter • Virginia M.‐Y. Lee • Disease Neuroimaging InitiativeActa Neuropath, 2011

and clinical performance of CSFand clinical performance of CSF alyses in ADNI

orzata Knapik Czajka • Michal Figurski • Elsorzata Knapik‐Czajka • Michal Figurski • ElsSimon • Piotr Lewczuk • Robert A. Dean • Eric John Q. Trojanowski • the Alzheimer’s 

Correlation of quantitation be

P <0.000r =0.9758

P <0.0001r =0.9886

etween J‐ADNI and US‐ADNIX‐axis：J‐ADNIX axis：J ADNIY‐axis：US‐ADNIIdentical J‐ADNI samples were measured at Niigata and Penn

18

Protocol― CSF: N=20 pa ents― analyzed at Niigata & Upenn― One lot # of INNO‐BIA AlzBio3 reagents(xMAP Luminex)g ( )Major findings― excellent correlation between centers― 2‐fold difference in A1‐42 but close agreement for t‐tau &

for p‐tau181181

P <0.0001r =0.9671

y = 1 003x 1 225t tau

Lab‐to‐lab comparisons of Lumine

y = 1.003x - 1.225R² = 0.982

100

150

200

250

pg/m

l

t-tau

0

50

100

0 50 100 150 200 250

May

o

UPenn pg/mlUPenn pg/ml

y = 1.189x R² = 0.8

566370

p-tau181

14212835424956

May

o pg

/ml

07

0 7 14 21 28 35 42 49 56 63

UPenn pg/ml

y = 1.136x + 4.845R² 0 910A1 42

ex/Innogenetics CSF immunoassay

R² = 0.910

200

300

400

500

o pg

/ml

A1-42

0

100

0 100 200 300 400 500

May

o

UPenn pg/mlUPenn pg/ml

- 2.083893 Protocol

― CSF: N=36― analyzed at Mayo & UPenn for this study― one lot # of INNO‐Bia AlzBio3 (xMAP, Luminex)Major findings― excellent correla on between the centers

70

excellent correla on between the centers― very good agreement in concentra ons (= low bias)

Quality control data for INNO‐BIA Plasma 

•Introduced an automated pipetting platform deve•2454 ADNI plasma samples (4,908 data points),72•%CV for plasma controls: 5.5‐7%, A1‐40 & 4.1‐5.2

Aqueous (ConA&B) & plasma (QC1, QC2) qc samples                 

A1‐40

A1‐40

A1‐42

A1‐42

A1‐40A1‐40

A1‐42A1‐42

the plasma A1‐42/1‐40Aß forms assayeloped in the ADNI biomarker core22 subjects from BL, 12, 24 up to 36 months% A1‐42; test/re‐test %CVs: 7.2% A1‐40, 4.5% A1‐42

                     Test/re‐test data

A1‐40 A1‐42

A1‐40  avg %CV=7.24%  A1‐42  avg %CV=4.51% 

Aβ LOAD CAN BE IMPUTED FROUNDERLINING THE CLOSE REL

COMPLEMENTARY METHODS FOR ASSUBJ

Transforming  CSF Aβ42 mPittsburgh compound B uPittsburgh compound B u

SD Weigand, P Vemuri, HJ Wiste, ML Senjem, VSLM Shaw, JQ Trojanowskif, DS Knopman, CR Jac

201

Conclusion: CSF Aβ42 can be transformamyloid load. Thus, brain Aβ amyloid loaAβ amyloid PET imaging and the data catechniques. q

OM CSF  AβMEASURES THEREBY LATIONSHIP BETWEEN THESE SSESSING Aβ PATHOLOGY  IN LIVING ECTS

measures into calculatednits of brain Aβ amyloid.nits of brain Aβ amyloid.S Pankratz, P S Aisen, MW Weiner, RC Petersen, ck Jr,  & ADNI. Alzheimer & Dementia, Online, 11 

ed into PIBcalc measures of Aβad can be ascertained by either CSF or an be pooled using imputation 

ADNI biomarker and autopsy studies wilbiomarker and postmortem studies reveal ab

l help clarify the relationship between what bout the onset and progression of AD pathologies

A. Modified from Braak et al, Acta Neuroapth, 82;239‐259 1991; 121:171‐259, 1991; 121:171‐181, 2011 from a  commentary by C. Duyckaerts, Acta Neuropath, 121:145‐147, 2011.

B. From Jack et al,B. From Jack et al, Lancet Neurol, 9:119‐128, 2010. 

THE CHALLENGES AHEAD: WHY DIS NO TR

“A Scary Idea: Pre-emptive BraFORBES, 7/15/2010 - Robert LanForbes, in charge of health care c

“You feel fine and have no symptoms, buy paway. And there is nothing we can do a

DIAGNOSE AD EARLY WHEN THEREEATMENT ?

ain Scans For Alzheimer's”ngreth is a senior editor at coverage

ut your brain is slowly rotting y y gbout it. Have a nice day.”

When Disease Modifying Therapies ArrivWill Be Ready Wi

Please  visit  LP Bistro next timeBistro next time you are at Philadelphia InternationalInternational Airport 

ve For AD, The Penn Biomarker Core ith LP Bistros! 

It takes a greaIt takes a grea

Leslie M. ShawVi i i M Y L

William HU      Alice Chen PlotVirginia M‐Y Lee

Chris ClarkSteve Arnold

Alice Chen PlotJon ToledoJu Hee KangUwe Christians

Hugo VandersticheleMagdalena KoreckaMargaret Knapik‐Czajka

Uwe ChristiansKaj BlennowHolly SoaresAdam SimonMargaret Knapik Czajka

Magdalena BrylskaTeresa WaligorskaMi h l Fi ki

Robert DeanEric SiemersPiotr Lewczuk

Michal FigurskiEls CoartRavi Patel

William Potter

Leona Fields

at team effort!at team effort!

       tkintkin

s

Supported by the NIH/NIA and familiesof our patients 

sADNI investigators include 

(complete listing available at www.loni.ucla.edu\ADNI\Collaboration\ADNI Manuscriptaboration\ADNI_Manuscript_Citations.pdf).